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PMID: 11032809 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

MAPK/ERK signaling in activated T cells inhibits CD95/Fas-mediated apoptosis downstream of DISC assembly.

The EMBO journal ·Vol. 19 ·No. 20 ·2000-10-16 ·Pages 5418-28

Holmström TH, Schmitz I, Söderström TS, Poukkula M, Johnson VL, Chow SC, Krammer PH, Eriksson JE

Abstract

When T cells are activated, the expression of the CD95 ligand is elevated, with the purpose of inducing apoptosis in target cells and to later eliminate the activated T cells. We have shown previously that mitogen-activated protein kinase (MAPK or ERK) signaling suppresses CD95-mediated apoptosis in different cellular systems. In this study we examined whether MAPK signaling controls the persistence and CD95-mediated termination of an immune response in activated T cells. Our results show that activation of Jurkat T cells through the T cell receptor immediately suppresses CD95-mediated apoptosis, and that this suppression is mediated by MAPK activation. During the phase of elevated MAPK activity, the activation of caspase-8 and Bid is inhibited, whereas the assembly of a functional death-inducing signaling complex (DISC) is not affected. These results explain the resistance to CD95 responses observed during the early phase of T cell activation and suggest that MAPK-activation deflects DISC signaling from activating caspase-8 and Bid. The physiological relevance of the results was confirmed in activated primary peripheral T cells, in which inhibition of MAPK signaling markedly sensitized the cells to CD95-mediated apoptosis.

MeSH Terms
Apoptosis/drug effects BH3 Interacting Domain Death Agonist Protein CASP8 and FADD-Like Apoptosis Regulating Protein CD3 Complex/immunology Carrier Proteins/metabolism Caspase 8 Caspase 9 Caspases/metabolism Cells, Cultured Enzyme Activation/drug effects Fas Ligand Protein Fluorescent Antibody Technique Humans Intracellular Signaling Peptides and Proteins Jurkat Cells Kinetics Lymphocyte Activation/drug effects MAP Kinase Signaling System/drug effects Membrane Glycoproteins/antagonists & inhibitors,immunology,metabolism Mitogen-Activated Protein Kinases/metabolism Muromonab-CD3/immunology,pharmacology Phosphorylation/drug effects Protein Biosynthesis Protein Processing, Post-Translational/drug effects Proto-Oncogene Proteins c-bcl-2/metabolism T-Lymphocytes/drug effects,enzymology,immunology,metabolism Tetradecanoylphorbol Acetate/pharmacology bcl-Associated Death Protein fas Receptor/immunology,metabolism
Chemicals
BAD protein, human BH3 Interacting Domain Death Agonist Protein BID protein, human CASP8 and FADD-Like Apoptosis Regulating Protein CD3 Complex CFLAR protein, human Carrier Proteins FASLG protein, human Fas Ligand Protein Intracellular Signaling Peptides and Proteins Membrane Glycoproteins Muromonab-CD3 Proto-Oncogene Proteins c-bcl-2 bcl-Associated Death Protein fas Receptor Mitogen-Activated Protein Kinases CASP8 protein, human CASP9 protein, human Caspase 8 Caspase 9 Caspases Tetradecanoylphorbol Acetate
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Holmström T H
Turku Centre for Biotechnology, University of Turku and Abo Akademi University, PO Box 123, FIN-20521 Turku, Finland.
Schmitz I
Söderström T S
Poukkula M
Johnson V L
Chow S C
Krammer P H
Eriksson J E
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/19.20.5418
Published
2000-10-16
Pages
5418-28
Language
English
Region
England
NLM ID
8208664
PMCID
PMC314013
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/19.20.5418 PMC Full Text View journal details
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